Enantiopure chiral intermediates are of major importance in the pharmaceutical and agrichemical industries. Such intermediates can be further elaborated to provide exclusively the biologically active enantiomer of a drug or crop protection chemical. This both eliminates waste in the manufacturing process and circumvents potential deleterious side-effects arising from the undesired enantiomer. W. A. Nugent et al., Science, 259, 479 (1993), R. Noyori, CHEMTECH, 22, 360 (1992). One potentially valuable class of chiral intermediate which has heretofore been unavailable are the enantiopure methylcycloalkenes. For example, the Nobel laureate E. J. Corey has noted the potential utility of enantiopure 3-methylcyclopentene and the derived trans-epoxide in asymmetric synthesis. E. J. Corey and X. Cheng, The Logic of Chemical Synthesis, John Wiley and Sons, New York, 1989.
Prior to the present invention, 3-methyl-cyclopentene had not been prepared selectively and with high enantiopurity. Acetoxylation of (R)-3-methylcyclopentanol, followed by pyrolysis at 530.degree. C. of the resulting acetate afforded a mixture of enantiopure (+)-(R)-3-methyl-cyclopentene and 4-methylcyclopentene in a 3:2 ratio; the mixture could not be separated by distillation (V. Schurig Israel Journal of Chemistry 1976/77, 15, 96). Kinetic resolution of racemic -methyl-cyclopentene by asymmetric hydroboration afforded material with low optical purity (Brown et al., 84, 4341; Waters et al., Tetrahedron Lett., 1968, 5233) . Asymmetric alkylation of an allylic ether gave 3-methylcyclopentene with very low optical purity (Congsiglio et al., Helv. Chim. Acta., 1980, 63, 987) .
The present invention makes possible the trivial synthesis of chiral cycloolefins selectively and in optical purities difficult or impossible to achieve by other routes. It is based on the ring-closing metathesis reaction of terpene derived, optically active dienes. Although intramolecular cyclization of dienes to give cycloolefins via metathesis is known, it has never been used to make optically active cycloolefins. The intramolecular cyclization of dienes containing two double bonds separated by five single bonds, to give cyclohexene, is well known. This literature is summarized in the book K. J. Ivin, Olefin Metathesis, Academic Press, London, 1983, Chapter 7.6. Ring-closing metathesis of dienes containing two double bonds separated by 4 single bonds, to give 5-membered rings, is not as well known (Finkel'shtein et al., Izv. Akad. Nauk SSR, Ser, Khim., 1981, 641; Kawai et al., 1984, 89, 452; Fu et al., J. Am. Chem. Soc., 1992, 114, 7324; Fu et al., J. Am. Chem. Soc., 1992, 114, 5426; Fu et al., J. Am. Chem. Soc., 1993, 115, 3800; Couturier et al., Angew. Chem. Int. Ed. Engl., 1993, 32, 112).
The present invention differs from the prior art in several respects. First, the product formed is optically active. Second, the double bonds of the diene undergoing ring-closing metathesis are highly hindered: one double bond is tri-substituted and the other may be one bond removed from a tertiary carbon atom, as is the case in .beta.-citronellene. Therefore, the reaction might have been anticipated to proceed in poor yield due to steric hindrance. In the prior art, the double bonds of dienes undergoing ring-closing metathesis are never more than disubstituted, and in fact are almost always monosubstituted. Thus, this invention differs from the prior art in that one of the olefins being formed in the reaction is isobutylene. Third, we disclose herein a highly active catalyst system [WOCl.sub.2 (O-2,6-C.sub.6 H.sub.3 -Br.sub.2).sub.2/MR .sub.4 ] for the ring-closing reaction that is very easy to prepare, in contrast to several other catalysts for this general type of reaction which require multiple steps to be synthesized (Fu et. al. J. Am. Chem. Soc. 1992, 114, 7324; Fu et. al. J. Am. Chem. Soc. 1992, 114, 5426; Fu et. al. J. Am. Chem. Soc. 1993, 115, 3800; Couturier et. al. Angew. Chem. Int. Ed. Engl. 1993, 32, 112).